1. Field of the Invention
The present invention relates generally to the field of drug delivery systems. In particular, the present invention relates to implantable osmotic pump systems.
2. Description of the Related Art
Since the beginning of modem medicine, drugs have been administered orally. Patients have taken pills as recommended by their physician. The pills must pass through the digestive system and then the liver before they reach their intended delivery site (e.g., the vascular system). The actions of the digestive tract and the liver typically reduce the efficacy of medication by about 33%. Furthermore, oral medications must be administered by the patient. Patient compliance to the prescribed delivery profile is often poor. Studies suggest that 40% of patients do not comply with their oral medication consumption instructions. This causes two concerns. First, patients who do not take their medication as instructed are not maintaining blood drug levels within the therapeutic window and are therefore not receiving adequate therapy for their disease. A second, worse scenario than receiving too little medication occurs when the patient may be taking too much medication either by accident or purposefully in order to make up for a missed dose. Both of these patient-controlled scenarios can be dangerous to the patient, and at a minimum may prolong or aggravate their disease. Subcutaneous drug delivery and intravenous drug delivery have the advantage of bypassing the acidic and enzymatic action of the digestive system. Unfortunately, IV administration requires the use of a percutaneous catheter or needle to deliver the drug to the vein. The percutaneous site requires extra cleanliness and maintenance to minimize the risk of infection.
Infection is such a significant risk that IV administration is often limited to a number of weeks, at most. In addition, the patient must wear an external pump connected to the percutaneous catheter if the therapy is intended to last longer than a few hours and the patient desires to be ambulatory. Subcutaneous drug delivery can be either partially implanted or totally implanted. Partially implanted systems rely on a percutaneous catheter or needle stick to deliver the medication, therefore, partially implanted systems have the same limitations as IV systems. Totally implanted systems have fewer maintenance requirements and are far less prone to infection than IV or partially implanted systems.
In the 1970s, a new approach toward sustained drug delivery was commercialized for animal use only. The driving force of such pumps was based upon a new approach utilizing the principle of osmosis. A recent example of such a pump is described listed in U.S. Pat. No. 5,728,396. This patent discloses an implantable osmotic pump that achieves a sustained delivery of leuprolide. The pump includes a right-cylindrical impermeable reservoir that is divided into a water-swellable agent chamber and a drug chamber, the two chambers being divided by a movable piston. Fluid from the body is imbibed through a semipermeable membrane into the water-swellable agent chamber. As the water-swellable agent in the water-swellable agent chamber expands in volume, it pushes on the movable piston, which correspondingly decreases the volume of the drug chamber and causes the drug to be released through a diffusion outlet at a substantially constant rate.
A limitation of the osmotic pump disclosed in the above-identified patent, however, is that its infusion rate cannot be adjusted once it is implanted. This is acceptable for medications that do not need rate adjustment, but often physicians desire to adjust the infusion rate based on the clinical status of the patient. One example of when a physician would want to increase the infusion rate is in the field of pain management. Osmotic pumps can be used to deliver medication to treat pain lasting over an extended period of time. Pain, however, often increases with time, and sometimes patients become tolerant to pain medications; therefore, more medication is needed to effectively treat the pain. The system disclosed in the above-identified patent does not allow a rate increase after implantation, so the physician must surgically remove the current implant and implant an additional pump to deliver the correct dosage. However, the prospect of yet another surgical procedure may cause many patients to forego the potential benefits of the larger dose and may also cause their physicians to advise against the initial procedure altogether.
The aspect ratio of such cylindrical osmotic pump delivery devices is large, and often not compatible with the human body. Indeed, the human body does not have naturally-formed right-cylindrical cavities in which to implant such devices in the patient, in an unobtrusive and comfortable manner.
What are needed, therefore, are improved osmotic pumps. What are also needed are improved implantable osmotic pumps that conform to the patient""s anatomy and that more closely match the =topology of the implant site. Also needed are novel implantable osmotic pumps for long term delivery of a pharmaceutical agent that do not rely upon a right-cylindrical pharmaceutical agent compartment and/or conventional cylindrical pistons. Also needed are implantable pumps that enable the physician to increase the dose of pharmaceutical agent delivered to the patient without, however, removing the pump from the implant site.
It is an object of the present invention, therefore, to provide improved pumps. Another object of the present invention is to provide improved implantable osmotic pumps that conform to the patient""s anatomy and that more closely match the topology of the implant site. A still further object is to provide novel implantable osmotic pumps for long term delivery of a pharmaceutical agent that do not rely upon a right-cylindrical pharmaceutical agent compartment and/or conventional cylindrical pistons. Preferably, such improved pumps should enable the physician to increase the dose of pharmaceutical agent delivered to the patient without removing the pump from the implant site.
In accordance with the above-described objects and those that will be mentioned and will become apparent below, an implantable osmotic pump for delivering a pharmaceutical agent to a patient, according to an embodiment of the present invention, includes an osmotic engine; a substantially toroidal compartment adapted to store a pharmaceutical agent, and a piston disposed within the compartment, the osmotic engine being configured to cause the piston to travel within the compartment and deliver the pharmaceutical agent when the pump is implanted in the patient.
The pump may include a tube coiled at least partially around the osmotic engine, an inner lumen of the tube defining the pharmaceutical agent compartment. The tube may include or be formed of metals, polymers and/or polyimid, for example. The compartment may be disposed at least partially around the osmotic engine. The tube may be rigid and the osmotic engine may be disposed within the tube.
According to other embodiments, the osmotic engine may include a base, a cylindrical wall attached to the base and a free end opposite the base. The pump may include a housing configured to enclose at least the osmotic engine and the tube. The housing may include a first housing half and a second housing half that mates with the first housing half. Each of the first and second housing halves may define a saucer shape, for example. Each of the first and the second housing halves may be substantially circular in shape. The first housing half may define a substantially circular opening. The pump may further include a membrane enclosure, the membrane enclosure being partially surrounded by the osmotic engine and including an initial dose semipermeable membrane that is configured to allow water from the patient to reach the osmotic engine when the pump is implanted. The pump may be configured to deliver an initial dose of the pharmaceutical agent to the patient at a selected initial infusion rate, the selected initial infusion rate being related to a thickness, a composition and/or a surface area of the initial dose semipermeable membrane. The initial dose semipermeable membrane may be fitted with an initial dose impermeable membrane that initially seals the initial dose semipermeable membrane.
A dose escalation assembly may be fitted in the membrane enclosure, the dose escalation assembly being adapted to selectively increase an amount of water from the patient that reaches the osmotic engine when the pump is implanted. The dose escalation assembly may include a first impermeable membrane configured to enable water from the patient to reach the osmotic engine through a first fluid path only after being breached. The dose escalation assembly may include a first impermeable membrane configured to enable water from the patient to reach the osmotic engine through a first fluid path only after being breached, and a second impermeable membrane configured to enable water from the patient to reach the osmotic engine through a second fluid path only after being breached, the first path being distinct from the second path. The first and second impermeable membranes may be disposed in the membrane enclosure in a stacked configuration wherein the first impermeable membrane must be breached before the second impermeable membrane can be breached. The first fluid path may include a first semipermeable membrane and the second fluid path may include a second semipermeable membrane that is distinct from the first semipermeable membrane. The pump may be configured to deliver a first dose of the pharmaceutical agent to the patient at a selected first infusion rate and a second dose of the pharmaceutical agent to the patient at a selected second infusion rate that is greater than the first infusion rate, the selected first and second infusion rates being related to a thickness, a composition and/or a surface area of the first and second semipermeable membranes, respectively.
The osmotic engine may include a hygroscopic salt and/or an absorbent polymer. The absorbent polymer may include a material selected from a group including poly(acrylic acid), potassium salt; poly(acrylic acid), sodium salt; poly(acrylic acid-co-acrylamide), potassium salt; poly(acrylic acid), sodium salt-graft-poly(ethylene oxide); poly (2-hydroxethyl methacrylate); poly(2-hydroxypropyl methacrylate) and poly(isobutylene-co-maleic acid) or derivatives thereof.
The tube-shaped compartment may have a substantially constant inner diameter over a length thereof. Alternatively, the tube-shaped compartment may have a non-constant inner diameter over a length thereof. The tube may be coiled at least twice around the osmotic engine. A layer of epoxy may encase at least the tube. The tube may include polyimid, for example. The tube may define a proximal end adjacent the osmotic engine and a distal end at an end opposite the proximal end, and the pump may further include a catheter coupled to the distal end. The catheter may include a radiopaque tip. The piston may include a sphere, an elastomeric cylinder and/or an elastomeric conical section and may include stainless steel, a refractory metal, plastic, nylon and/or rubber, for example.
The tube-shaped compartment may be pre-loaded with a volume of the pharmaceutical agent. For example, the pharmaceutical agent may be therapeutically effective for pain therapy, hormone therapy, gene therapy, angiogenic therapy, anti-tumor therapy, chemotherapy, allergy therapy, hypertension therapy, antibiotic therapy, bronchodilation therapy, asthmatic therapy, arrhythmia therapy, nootropic therapy, cytostatic and metastasis inhibition therapy, migraine therapy, gastrointestinal therapy and/or other pharmaceutical therapies.
The dose escalation assembly may include a first saturated saline solution between the first impermeable membrane and the first semipermeable membrane, and a second saturated saline solution between the second impermeable membrane and the second semipermeable membrane.
The present invention is also a kit, comprising an implantable osmotic pump for delivering a pharmaceutical agent to a patient, including an osmotic engine, a tube coiled around the osmotic engine, the tube defining an inner tube-shaped compartment adapted to store a pharmaceutical agent, and a piston disposed within the tube-shaped compartment, the osmotic engine being configured to exert a force on the piston to cause the piston to travel within the tube-shaped compartment and deliver the pharmaceutical agent when the pump is implanted in the patient, and a catheter configured to attach to the pump. The pump may further include a membrane enclosure, the membrane enclosure being partially surrounded by the osmotic engine and an initial dose semipermeable membrane that is configured to allow water from the patient to reach the osmotic engine when the pump is implanted. The pump may further include a dose escalation assembly fitted in the membrane enclosure, the dose escalation assembly being adapted to selectively increase an amount of water from the patient that reaches the osmotic engine when the pump is implanted. The dose escalation assembly may include a first impermeable membrane configured to enable water from the patient to reach the osmotic engine through a first fluid path only after being breached, and a second impermeable membrane configured to enable water from the patient to reach the osmotic engine through a second fluid path only after being breached, the first path being distinct from the second path. The kit may further include a dose escalation pen configured to breach the first and/or second impermeable membranes. The dose escalation pen may include a dose selection actuator that is adapted to re-configure the dose escalation pen to selectively breach one of the first and second impermeable membranes. The tube-shaped compartment may be pre-loaded with the pharmaceutical agent.
The present invention is also a method of delivering a pharmaceutical agent to a patient, comprising steps of implanting a pump into the patient, the pump including a pump engine and a compartment adapted to store a pharmaceutical agent, the compartment defining at least a partial torus around the osmotic engine, and causing a piston to travel a distance within the compartment and to deliver a dose of pharmaceutical agent corresponding to the distance traveled out of the compartment. The implanting step may implant the pump (and/or portions thereof) intravascularly, subcutaneously, epidurally, intrathecally and/or intraventricularly, for example. A step of selectively increasing the dose in a stepwise manner over a treatment period without removing the pump from the patient may also be carried out. The pump engine may include an osmotic engine and the pump may include an initial dose semipermeable membrane initially exposed to the patient and at least one second semipermeable membrane initially not exposed to the patient. The increasing step may then include a step of selectively exposing the at least one second semipermeable membrane to the patient. The pump the engine may include an osmotic engine in fluid communication with the piston and the causing step may include a step of increasing a volume of the osmotic engine.
The present invention is also a pump, comprising a pump engine; a tube coiled around the engine, the tube defining an inner tube-shaped compartment adapted to store a fluid, and a piston disposed within the tube-shaped compartment, the engine being adapted to cause the piston to travel within the tube-shaped compartment and to force a dose of the fluid out of the pump. The pump engine may include an osmotic engine. The fluid may include a pharmaceutical agent. A catheter may be coupled to the tube. The pump may be fully implantable in a body and the pump engine and the tube may be enclosed in a biocompatible pump housing. The pump may include a dose escalation assembly, the escalation assembly being configured to selectively increase the dose of fluid delivered. The dose escalation assembly may comprise means for increasing the dose delivered in a stepwise manner. The piston may include a sphere, an elastomeric cylinder and/or an elastomeric conical section, for example.
According to another embodiment thereof, the present invention is an osmotic pump, comprising an osmotic engine and a pump housing enclosing the osmotic engine and defining a substantially toroidal space adapted to contain a volume of pharmaceutical agent. The pump housing may define a substantially circular outline. The substantially toroidal space may define an inner and an outer radius, and the osmotic engine may be disposed within the inner radius. The pump may include a tube disposed within the toroidal space, the tube defining an inner lumen adapted to contain the volume of pharmaceutical agent. Alternatively, the pump housing may include a first housing half and a second housing half, the first and second housing halves defining, when mated together, the substantially toroidal space, the substantially toroidal space being fluid tight. The pump may further include a semipermeable membrane enclosure and a semipermeable membrane fitted within the semipermeable membrane enclosure. A single semipermeable membrane may be fitted within the semipermeable membrane enclosure, in which case, the pump is a single stage pump. Alternatively, the pump may be an n-stage pump and the semipermeable membrane enclosure may be fitted with n semipermeable membranes, each of the n stages being configured to be selectively activated after implantation of the pump. The pump may also include an OFF switch mechanism configured to be selectively activated after implantation of the pump. The pump may also include a filter assembly to filter the pharmaceutical agent. The filter assembly may include a plug of porous material, the porous material defining pores selected to have an average size of between about 2 microns and about 80 microns. For example, the filter assembly may include a plug of porous material, the porous material being hydrophilic or hydrophobic (or having hydrophilic or hydrophobic characteristics).
The present invention is also an implantable osmotic pump, comprising a semipermeable membrane; a housing adapted to enclose a volume of pharmaceutical agent and a portion of the semipermeable membrane; an osmotic engine adapted to cause the pharmaceutical agent to be delivered out of the pump as an osmotic pressure differential develops across the semipermeable membrane, and an OFF switch, the OFF switch being effective to reduce the osmotic pressure differential across the semipermeable membrane substantially to zero, and/or an ON switch, the ON switch being effective to enable the pump to begin to deliver the pharmaceutical agent out of the pump. The OFF switch may include an OFF switch impermeable membrane and the OFF switch may be configured to turn the pump OFF (reduce the osmotic pressure substantially to zero) only when the OFF switch impermeable membrane is breached. The OFF switch may define a lumen adapted to allow fluid to bypass the semipermeable membrane when the OFF switch impermeable membrane is breached. The ON switch may include an impermeable membrane disposed over the semipermeable membrane, the pump being turned ON (adapted to begin delivery of the pharmaceutical agent) only after the impermeable membrane is breached. A volume of saturated saline solution may be disposed between the semipermeable membrane and the impermeable membrane.
The pharmaceutical agent compartment of the pump may contain Sufentanil, for example, and/or may contain other medications. The sufentanil may be at a concentration of up to about 500,000 xcexcg/mL. The pharmaceutical agent may include Sufentanil and the pump may be configured for a daily delivery rate of Sufentanil of up to about 25 micrograms per day when the pump is configured to be implanted intraventricularly; a daily delivery rate of Sufentanil of up to about 50 micrograms per day when the pump is configured to be implanted intrathecally; a daily delivery rate of Sufentanil of up to about 500 micrograms per day when the pump is configured to be implanted epidurally; a daily delivery rate of Sufentanil of up to about 1500 micrograms per day when the pump is configured to be implanted subcutaneously, and a daily delivery rate of Sufentanil of up to about 1500 micrograms per day when the pump is configured to be implanted intravascularly. The catheter and the pump may be dimensioned to infuse a dose of pharmaceutical agent of up to about 1500 xcexcg/day over a treatment period, for example.
According to another embodiment thereof, the present invention is also a filter assembly for an osmotic pump, the filter defining a first end configured to mate with the osmotic pump a second end configured to be exposed, in use, to an aqueous environment and including a filter between the first and second ends. The filter may include a porous material, the porous material defining pores selected to have an average size of between about 2 microns and about 80 microns. The plug of porous material may be hydrophilic or hydrophobic (or have hydrophobic or hydrophilic properties).